Lupus (Chen, 2020) – Is lupus genetic?

Nebula Genomics DNA Report for Lupus

Is lupus genetic? We created a DNA report based on a study that attempted to answer this question. Below you can see a SAMPLE DNA report. To get your personalized DNA report, purchase our Whole Genome Sequencing!

A sample report for lupus from Nebula Genomics
A sample report on lupus genetic variants from Nebula Genomics
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This information has been updated to reflect recent scientific research as of April 2021.

Additional Information

What is lupus? (Part 1 of Is lupus genetic?)

Lupus is a rare, chronic (long term), autoimmune disease. In healthy people, proteins called antibodies protect the body by attacking foreign invaders. When a person has this condition, the antibodies cannot tell the difference between foreign material and healthy cells. Thus, the immune system attacks healthy tissue. These autoantibodies cause inflammation, pain, and damage in various parts of the body. The most common areas affected are skin, joints, and internal organs like the kidneys and heart. 

The disease can occur in various forms. The types of lupus are: 

  • Systemic lupus erythematosus (SLE) – a rheumatic disease in the collagenosis group and can affect all organs
  • Cutaneous lupus erythematosus (CLE) – this form of lupus is a dermatologic condition that usually only affects the skin. Although the rashes do not normally hurt or itch, they may become discolored. The affected areas can also be photosensitive. 
    • Discoid lupus – appears as a skin rash consisting of disk-shaped, round lesions. The sores usually appear on the scalp and face as red, scaly, and thick lesions. 
    • Subacute cutaneous lupus – lesions may appear as areas of red scaly skin with distinct edges or as red, ring-shaped lesions. They usually occur on the sun-exposed areas of the arms, shoulders, neck, and body. 
    • Acute cutaneous – a malar rash–flattened areas of red skin on the face that resemble a sunburn. It usually appears as a “butterfly rash” on the cheeks and nose although may appear on other areas as well. 
  • Neonatal lupus erythematosus – occurs in newborns born to mothers with lupus
  • Drug-induced lupus – a lupus-like disease caused by certain prescription drugs
Antibody-antigen complexes
In autoimmune disorders, antibodies can attack and damage healthy cells. Alejandro Porto. Attribution-Share Alike 3.0 Unported.  

People with lupus may have a family history of the disease or other immune disorders. The condition usually progresses in relapses. Between relapses, there may be long phases in which the disease is not active or only slightly active. Particularly characteristic of lupus is butterfly erythema, a redness that extends symmetrically from the bridge of the nose to the zygomatic and cheek regions.

Is lupus inherited?

Variants in many genes can affect the risk of developing lupus, and in most cases multiple genetic factors are thought to be involved. Most of the genes associated with lupus are involved in immune system function, and variations in these genes likely affect proper targeting and control of the immune response. 

Some gene variations that have been linked to lupus include IRF5, NCF2, PTPN22, STAT4, and TREX1

IRF5: Produces a protein that acts as a transcription factor to regulate certain genes’ activities that produce interferons and other cytokines. Cytokines promote inflammation and control other parts of the immune system when an infection is present. They also stimulate the activity of certain immune cells called natural killer cells. 

NCF2: Produces a subunit of a protein that helps regulate the immune system, namely immune cells called phagocytes that catch and destroy foreign invaders. This protein also plays a role in regulating neutrophils, which adjust the body’s inflammatory response to injury.

PTPN22: Creates PTP proteins that regulate signal transduction, a process that relays messages from outside of the cell to the cell nucleus. They are involved in signaling that helps regulate immune cells called T cells, which identify foreign substances and helps protect the body from infection.

STAT4: Like IRF5, this gene produces a transcription factor. When activated, this protein enhances the activity of genes that help immune cells called T-cells mature into specialized T-cells.

TREX1: Produces an enzyme that trims molecules of DNA (DNA exonuclease). It removes unneeded DNA fragments that may have been created during replication. 

Current Research on Lupus (Updated May 2021)

Lupus is not curable, but it can be treated with medication. There is ongoing research on it, many of it cataloged in this PubMed curation of tens of thousand studies of the disease. After a decade of having only one treatment approved in half a century, 2020 saw a rebirth of investigation on the condition. 

This resulted in the approval of therapies to treat lupus nephritis (a severe kidney complication), most recently Voclosporin. After two years of a controlled trial of intravenous Belimumab, results showed that patients who received it had a primary efficacy renal response. 

To better understand the relationship between genes and lupus, we need to find the genetic markers that predispose it. This “Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus” is a positive path in that direction. This type of research is done in the hopes of preventing the disease from developing in the first place.

A 2019 article in Science Magazine reported that a treatment known to have successfully treated certain leukemias in children and lymphomas in adults in 2012 had been used to wipe out the condition in mice. This therapy is known as chimeric antigen receptor (CAR)-T and was applied to 26 mice whose spleens, skin, kidneys, and other body parts recovered from lupus.

Epidemiology (Part 4 of Is lupus genetic?)

The condition can affect people of all ages, including children. However, women of childbearing age (15 to 44 years) are at higher risk than the general population. In fact, 9 out of 10 people with lupus are women.  

According to the Lupus Foundation of America, an estimated 1.5 million Americans and at least five million people worldwide are affected by lupus. 

Recent national estimates of prevalence and incidence are not available for systemic lupus. Lack of data can be contributed to the fact that SLE is relatively uncommon, is difficult to diagnose, and is not a reportable disease. There are no recent studies to determine if SLE prevalence or incidence are changing over time.

A conservative estimate from 2008 suggests a prevalence of 161,000 with definite SLE and 322,000 with definite or probable SLE.

Certain ethnic groups, including Black, Asian/Pacific Islander, and Hispanic populations, are more susceptible to developing lupus and at higher risk of developing more severe symptoms. The condition also appears to be more prevalent in Native American populations, with earlier ages of onset, higher rates of autoantibodies, and different clinical patterns than other populations. 

According to the CDC and National Center for Health Statistics, SLE was identified as the underlying cause of death for an average of 1,176 deaths per year from 2010–2016.

Characteristics and Symptoms (Part 5 of Is lupus genetic?)

Characteristics

The symptoms of lupus are different for each individual. They may come on suddenly or gradually and range from mild to severe. Many people experience episodes, or flares, in which symptoms grow worse for a time before improving or even disappearing. 

Symptoms

The characteristics depend on which parts of the body the disease is affecting. Some of the most common symptoms include:

  • Fatigue
  • Fever
  • Joint pain, stiffness and swelling
  • Butterfly-shaped rash on the face that covers the cheeks and bridge of the nose or rashes elsewhere on the body
  • Skin lesions that appear or worsen with sun exposure (photosensitivity)
  • Fingers and toes that turn white or blue when exposed to cold or during stressful periods (Raynaud’s phenomenon)
  • Shortness of breath
  • Chest pain
  • Dry eyes
  • Headaches, confusion and memory loss
Signs and symptoms of lupus including internal and external symptoms
Signs and symptoms of lupus. CNX OpenStax. Attribution 4.0 International.

Causes (Part 6 of Is lupus genetic?)

A combination of genetics and environmental triggers contribute to the onset of the disease.

In the lupus erythematosus forms, the normal immune system is dysregulated. It is permanently activated and persistently produces an increased number of antibodies against the body’s own cell nuclear components, so-called antinuclear antibodies (ANA). These autoantibodies damage the body’s own cells.

As cells die, they release their nuclear components. The immune system reacts to the cell nuclear components of healthy endogenous cells that are falsely recognized as foreign, and activation of the endogenous immune system and production of more antinuclear antibodies occurs. The activation of the immune system triggers an inflammatory reaction, causing additional body tissue damage. 

Immune complexes are formed from cell nuclear components and autoantibodies in ways that increase arteriosclerosis and lead to vasoconstriction or vascular occlusion, so that the organs or organ systems are only inadequately supplied with blood and can be additionally damaged. Inflammatory reactions caused by the deposition of immune complexes on the blood vessel walls can also occur. 

The exact cause of this pathological reaction of the immune system is as yet unknown. However, it is assumed, among other things, that an increased interferon activity of type I interferon plays an important role. 

In cutaneous lupus erythematosus, only the skin is affected. However, CLE can progress into systemic lupus.. 

According to Mayo Clinic, it is suspected that people with a genetic predisposition develop the disease when they experience an environmental trigger. Potential triggers include: 

  • Sunlight – exposure to the sun may bring on skin lesions or trigger an internal response in susceptible people
  • Infections – having an infection can initiate the condition or cause a relapse in some people
  • Medications – it can be triggered by certain types of blood pressure medications, anti-seizure medications, and antibiotics. People who have drug-induced lupus usually get better when they stop taking the medication. Rarely, symptoms may persist even after drug use stops. About 10 percent of SLE cases are thought to be triggered by drug exposure, and more than 80 drugs that may be involved have been identified

Diagnosis (Part 7 of Is lupus genetic?)

If lupus is suspected, a doctor will usually first check for signs of inflammation, including pain, heat, redness, swelling, and loss of function at a particular place in the body. Diagnosis is difficult since the symptoms mimic those of many other diseases. The most distinctive sign of lupus – a facial rash that resembles butterfly wings unfolding across both cheeks – occurs in many but not all cases of lupus.

According to the Lupus Foundation of America, diagnosis will include the following review with a physician:

  • Current symptoms
  • Laboratory test results
  • Medical history
  • Medical history of your close family members (grandparents, parents, brothers and sisters, aunts, uncles, cousins)

A variety of laboratory and blood tests may be used to help diagnosis, but no single test can give a definitive answer. The most common lab test associated with lupus is called the antinuclear antibody (ANA) test. This test detects antinuclear antibodies (antibodies that attack cellular nuclei) in the blood. A problem is that the ANA test is not specifically for lupus. It is also used to diagnose rheumatoid arthritis, Scleroderma (a rare disease affecting the skin, joints, and blood vessels), and Sjogren’s syndrome (a rare disease affecting the body’s moisture-making glands).

Blood tests
There is no single lab test to positively diagnose lupus. GrahamColm. Attribution-Share Alike 3.0 Unported.

Often, a professional rheumatologist may need to be consulted to obtain a more confident diagnosis and prescribe a treatment plan.

Treatment (Part 8 of Is lupus genetic?)

While there is no cure for lupus, diagnosis and treatments can be used to prevent flares, treat symptoms, and reduce organ damage. The potential medicines prescribed are used to reduce pain and swelling, calm the immune system, reduce or prevent joint damage, and/or reduce or prevent organ damage. 

Some medicines to help patients cope with lupus and improve quality of life include:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) – over-the-counter NSAIDs, such as ibuprofen and naproxen, help reduce mild pain and swelling in joints and muscles
  • Corticosteroids – these medicines reduce swelling, tenderness, and pain. In high doses, they can calm the immune system
  • Antimalarial drugs – these will treat joint pain, skin rashes, fatigue, and lung inflammation. Two common antimalarial medicines are hydroxychloroquine (Plaquenil) and chloroquine phosphate (Aralen)
  • BLyS-specific inhibitors – these drugs limit the number of abnormal B cells (cells in the immune system that create antibodies) found in people with lupus. A common type of BLyS-specific inhibitor that treats lupus symptoms, belimumab, blocks the action of a specific protein in the body that is important in immune response
  • Immunosuppressive agents/chemotherapy. These medicines may be used in severe cases of lupus, when it affects major organs and other treatments do not work
  • Other medicines. Many people with lupus are also at risk for high blood pressure and blood clots, which can cause a stroke or heart attack. Your doctor may prescribe anticoagulants, or blood thinners, such as warfarin or heparin, to prevent your blood from clotting too easily

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